Transdermal Drug Delivery System

ABSTRACT

Provided herein is a water- and sweat-resistant transdermal drug delivery system for application to the skin of a mammal that comprises a patch having a diameter between 1 and 8 cm in length and a surface area between 4 and 8 cm 2 . Also provided are methods of producing the transdermal drug delivery system and methods of treatment comprising the use of the transdermal drug delivery system.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.62/543,580, filed on Aug. 10, 2017.

FIELD

Provided herein are water- and sweat-resistant transdermal drug deliverysystems for application to the skin of a mammal, that are notskin-irritating and are particularly suitable for use in subjects withsensitive skin. The disclosed transdermal delivery systems comprise apatch having a small size to allow delivery of large amounts of activeagents, while minimizing the surface area of skin required foradministration, a quick onset of action, sustainable drug delivery for8-24 hours, and adhesive strength. Also provided are methods of makingthe disclosed transdermal drug delivery systems, and methods of usingthe transdermal delivery systems to treat allergic reactions, disordersof the immune system and cardiovascular diseases.

BACKGROUND

Transdermal drug delivery represents an attractive alternative to oraladministration, especially where extended and consistent delivery isdesired, and where the replacement of oral tablets and pills isnecessary to ensure patient compliance, such as in pediatric and elderlypopulations.

Transdermal drug delivery provides the advantage of bypassing livermetabolism of drugs, which presents a challenge with the oraladministration of drugs. In addition, transdermal drug delivery ispain-free and non-invasive, can be self-administered and providesrelease for long periods of time. However, only a limited number ofdrugs are amenable to transdermal administration. While currenttransdermal delivery devices may successfully deliver lipophilic smallmolecule drugs, it remains difficult to transdermally deliverhydrophilic drugs through the skin and into the bloodstream. Therefore,a need exists for transdermal delivery drug systems that can sustainablydeliver lipophilic, hydrophilic and amphiphilic drugs, are quick to actand do not irritate the skin.

SUMMARY

It is shown herein that large molecule and small molecule drugs may besuccessfully delivered transdermally into the bloodstream. Based onthese findings, a water- and sweat-resistant transdermal drug deliverysystem for application to the skin of a mammal is provided. The water-and sweat-resistant transdermal drug delivery system comprises a patchhaving a diameter between 1 and 8 cm in length and a surface areabetween 4 and 8 cm². The patch comprises a monolithic layer of about 1to 5 mm in width, wherein the monolithic layer comprises 10-30% (w/w) ofa bioadhesive polymer; 10-40% (w/w) of a film-forming agent; 10-60%(w/w) of a plasticizer; 1-20% (w/w) of a naturally occurringpolysaccharide; 10-50% (w/w) of a keratolytic agent; and 1-60% (w/w) ofone or more active agents. The patch has an onset of action within 15minutes of application to the skin of a mammal, and it sustainablydelivers on or more active agents for 8-24 hours. The patch hasexcellent adhesive strength, as shown by a peel rate of about 320mm/min.

In some examples, the bioadhesive polymer may include chitosan,hydroxypropylmethyl cellulose, hydroxyethyl cellulose, xanthan gum, guargum, sodium alginate, or a combination thereof. In some examples, thefilm-forming agent may include polyvinyl alcohol, polyvinyl pyrrolidone,carrageenan, gelatin, dextrin, polyethylene oxide, guar gum, xanthangum, or a combination thereof. In some additional examples, theplasticizer may include glycerol, sorbitol, polyethylene glycol,polypropylene glycol, polyethylene-propylene glycol, or a combinationthereof. In some other examples, the naturally occurring polysaccharidemay include agar, alginate, chitin, glucomannan, gellan gum, gelatin,gum guar, gum Arabic, locust bean gum, pectin, xanthan, or a combinationthereof. In some examples, the keratolytic agent may include urea,lactic acid, allantoin, benzoyl peroxide, salicyclic acid, or acombination thereof. Thus, in one example, the monolithic layer maycomprise 10-30% (w/w) chitosan; 10-40% (w/w) polyvinylpyrrolidone;10-60% glycerol; 1-20% (w/w) gum Arabic; and 10-50% (w/w) lactic acid.

In some examples, the water- and sweat-resistant transdermal drugdelivery system provided herein may further comprise circular adhesivebacking layer. Suitable materials for the backing layer include, but arenot limited to, Teflon, metal foils, metalized polyfoils, compositefoils or films containing polyester, such as polyester terephthalate,polyester or aluminized polyester, polytetrafluoroethylene, polyetherblock amide copolymers, polyethylene methyl methacrylate blockcopolymers, polyurethanes, polyvinylidene chloride, nylon, siliconeelastomers, rubber-based polyisobutylene, styrene, styrene-butadiene andstyrene-isoprene copolymers, polyethylene, and polypropylene.Additionally, the backing layer may include various foams, such as, butnot limited to, polyolefin foams, polyvinyl chloride foams, polyurethanefoams, and polyethylene foams.

The water- and sweat-resistant transdermal drug delivery system providedherein may deliver a great variety of active agents into the skin. Insome example, only one active agent at the time is delivered into theskin. In other examples, a combination of active agents is deliveredinto the skin, either sequentially or contemporaneously. Examples ofactive agents include, but are not limited to, one or moreantihistamines, potassium channel blockers, analgesic agents,antidiabetic agents, pain-relief agents, antidepressant agents,antipsychotic agents, anti-Parkinsonian agents, vasodilators, diuretics,calcium channel blockers, anti-acne agents, anti-aging agents,antibiotic agents, antifungal agents, ACE inhibitors, GERD medications,anti-inflammatory agents, opioids, anti-asthma agents, corticosteroids,nicotinic cholinergic receptor agonists, anti-oxidant agents,antiprotozoal agents, antipruritic agents, antiviral agents,chemotherapeutic agents, immunomodulatory agents, keratolytic agents,retinoids, and central nervous system stimulants.

Exemplary antihistamines include, but are not limited to,Diphenhydramine, Loratadine, Desloratadine, and Cetirizine. Exemplaryantidepressants and anti-anxiety agents include, but are not limited to,Sertraline, Fluoxetine, Paroxetine, Venlaxafine, Duloxetine,Escitalopram Oxalate, Alprazolam, and Lorazepam. Exemplary ADHDmedications include, but are not limited to, amphetamine aspartate,dextroamphetamine, methylphenidate hydrochloride, dexmethylphenidatehydrochloride, and amitriptyline. Exemplary Anti-Parkinson's medicationsinclude, but are not limited to, Levodopa, Carbidopa, Ropinirole,Pramipexole, Rotigotine, Apomorphine, Selegine Hydrochloride,Rasagiline, and Benztropine. Exemplary Multiple Sclerosis Medicationsinclude, but are not limited to, Teriflunomide, Dalfampridine, DimethylFumarate, Natalizumab, Fingolimod, and Glatiramer Acetate. ExemplaryAlzheimer's Medications include, but are not limited to, Donezepil,Rivastigmine, and Galantamine. Exemplary analgesics include, but are notlimited to, Methadone, Hydromorphone, Oxymorphone, Buprenorphine,Hydrocodone, Morphine, and Hydrocodone. Exemplary GERD medicationsinclude, but are not limited to, esomeprazole, omeprazole, andpantoprazole. Exemplary anti-cholesterol agents include, but are notlimited to, ondansentron, pioglitazone, orlistat, lenalidomide,sofusbovir, rosuvastatin, amlodipine, simvastatin, and metformin.

In some examples, the active agent is one or more of diphenhydramine,Desloratadine, Cetirizine, Loratadine, Trihexyphenidyl, Asenapine,Prostacyclin, Buspirone, Butorphanol, Captopril, Carbidopa, Albuterol,Naltrexone, Ivabradine, Dexamethasone, Phenylephrine, Fluocinoloneacetonide, Dexlansoprazole, Furosemide, Isradipine, Venlafaxine, andEnalapril.

Also provided herein is a water- and sweat-resistant transdermal drugdelivery system that comprises a patch that is occlusive to one or moremolecules. These molecules include, but are not limited to, caffeine,aripiprazole, theophylline, dyphilline, pentoxifyline, enprofylline,aminophylline, oxtriphylline, theobromine, propentofylline, xanthinol,doxofylline, pamabrom, lisofylline, ganciclovir, fenethylline, xanthine,uric acid, rolofylline, reproterol, cafedrine and theodrenaline, and anycombination thereof.

The water- and sweat-resistant transdermal drug delivery system providedherein presents several attractive features and desirable propertiesthat make it suitable for use in a variety of mammal subjectsubpopulations, such as human subpopulations. For example, allcomponents of the patch are not irritating to the skin and cause norash, redness, inflammation or discoloration of the skin, making thewater- and sweat-resistant transdermal drug delivery system particularlysuitable to the elderly and pediatric populations, who tend to havesensitive skin.

In addition, because of the small size of the patch, the water- andsweat-resistant transdermal drug delivery system provided herein enableslarge surface-to-volume ratio to deliver large amounts of drugs andminimize the surface area of the skin required for administration, hasan onset of action within 5 to 15 minutes, and allows about 65% to about100% of one or more drugs to diffuse into the skin of a mammal within 8to 24 hours. Thus, the water- and sweat-resistant transdermal drugdelivery system provided herein provides a dosage form that achievesquick delivery through the skin into the bloodstream, reduces commonside effects and improves patient compliance.

Also provided herein is a method of making a water- and sweat-resistanttransdermal drug delivery system. The method comprises first adding afilm-forming agent and a plasticizer to water and stirring the mixtureat room temperature (25° C.); gradually adding a bioadhesive polymer anda naturally occurring polysaccharide and stir the mixture until thebioadhesive polymer is dissolved and viscosity is reduced; then adding afilm-forming agent and a keratolytic agent and stirring for 2-5 hoursuntil an even mixture is obtained; adding one or more active agents andstirring the mixture for 1-4 hours to obtain a formulation; andoptionally casting the formulation onto an array of backing layers andbaking the backing layers at 80° C. for 4-8 hour.

In some examples, the bioadhesive polymer may include chitosan,hydroxypropylmethyl cellulose, hydroxyethyl cellulose, xanthan gum, guargum, sodium alginate, or a combination thereof. In some examples, thefilm-forming agent may include polyvinyl alcohol, polyvinyl pyrrolidone,carrageenan, gelatin, dextrin, polyethylene oxide, guar gum, xanthangum, or a combination thereof. In some additional examples, theplasticizer may include glycerol, sorbitol, polyethylene glycol,polypropylene glycol, polyethylene-propylene glycol, or a combinationthereof. In some examples, the naturally occurring polysaccharide mayinclude agar, alginate, chitin, glucomannan, gellan gum, gelatin, gumguar, gum Arabic, locust bean gum, pectin, xanthan, or a combinationthereof. In some examples, the keratolytic agent may include urea,lactic acid, allantoin, benzoyl peroxide, salicyclic acid, or acombination thereof. In one example, the patch may comprise 10-30% (w/w)chitosan; 10-40% (w/w) polyvinylpyrrolidone; 10-60% glycerol; 1-20%(w/w) gum Arabic; and 10-50% (w/w) lactic acid.

In some examples, the patch may comprise a backing layer. Suitablematerials for the backing layer include, but are not limited to, Teflon,metal foils, metalized polyfoils, composite foils or films containingpolyester, such as polyester terephthalate, polyester or aluminizedpolyester, polytetrafluoroethylene, polyether block amide copolymers,polyethylene methyl methacrylate block copolymers, polyurethanes,polyvinylidene chloride, nylon, silicone elastomers, rubber-basedpolyisobutylene, styrene, styrene-butadiene and styrene-isoprenecopolymers, polyethylene, and polypropylene. Additionally, the backinglayer may include various foams, such as, but not limited to, polyolefinfoams, polyvinyl chloride foams, polyurethane foams, and polyethylenefoams.

In some examples, the provided method may further comprise adding 2-15%(w/w) of one or more fatty acids. The fatty acids include, but are notlimited to, tartaric acid, oleic acid, lauric acid, maleic acid, and anycombination thereof. In some examples, the provided method may furthercomprise adding 2-15% (w/w) of one or more essential oils. Essentialoils include, but are not limited to, L-menthol, chuanxiong oil, cloveoil, cinnamon oil, turpentine oil, eucalyptus oil, and any combinationthereof.

The provided method produces a water- and sweat-resistant transdermaldrug delivery system that may deliver a great variety of active agentsinto the skin. In some example, only one active agent at the time isdelivered into the skin. In other examples, a combination of activeagents is delivered into the skin, either sequentially orcontemporaneously. Examples of active agents include, but are notlimited to, one or more antihistamines, potassium channel blockers,analgesic agents, antidiabetic agents, pain-relief agents,antidepressant agents, antipsychotic agents, anti-Parkinsonian agents,vasodilators, diuretics, calcium channel blockers, anti-acne agents,anti-aging agents, antibiotic agents, antifungal agents, ACE inhibitors,GERD medications, anti-inflammatory agents, opioids, anti-asthma agents,corticosteroids, nicotinic cholinergic receptor agonists, anti-oxidantagents, antiprotozoal agents, antipruritic agents, antiviral agents,chemotherapeutic agents, immunomodulatory agents, keratolytic agents,retinoids, and central nervous system stimulants.

Exemplary antihistamines include, but are not limited to,Diphenhydramine, Loratadine, Desloratadine, and Cetirizine. Exemplaryantidepressants and anti-anxiety agents include, but are not limited to,Sertraline, Fluoxetine, Paroxetine, Venlaxafine, Duloxetine,Escitalopram Oxalate, Alprazolam, and Lorazepam. Exemplary ADHDmedications include, but are not limited to, amphetamine aspartate,dextroamphetamine, methylphenidate hydrochloride, dexmethylphenidatehydrochloride, and amitriptyline. Exemplary Anti-Parkinson's medicationsinclude, but are not limited to, Levodopa, Carbidopa, Ropinirole,Pramipexole, Rotigotine, Apomorphine, Selegine Hydrochloride,Rasagiline, and Benztropine. Exemplary Multiple Sclerosis Medicationsinclude, but are not limited to, Teriflunomide, Dalfampridine, DimethylFumarate, Natalizumab, Fingolimod, and Glatiramer Acetate. ExemplaryAlzheimer's Medications include, but are not limited to, Donezepil,Rivastigmine, and Galantamine. Exemplary analgesics include, but are notlimited to, Methadone, Hydromorphone, Oxymorphone, Buprenorphine,Hydrocodone, Morphine, and Hydrocodone. Exemplary GERD medicationsinclude, but are not limited to, esomeprazole, omeprazole, andpantoprazole. Exemplary anti-cholesterol agents include, but are notlimited to, ondansentron, pioglitazone, orlistat, lenalidomide,sofusbovir, rosuvastatin, amlodipine, simvastatin, and metformin.

In some examples, the active agent is on or more of Diphenhydramine,Desloratadine, Cetirizine, Loratadine, Trihexyphenidyl, Asenapine,Prostacyclin, Buspirone, Butorphanol, Captopril, Carbidopa, Albuterol,Naltrexone, Ivabradine, Dexamethasone, Phenylephrine, Fluocinoloneacetonide, Dexlansoprazole, Furosemide, Isradipine, Venlafaxine, andEnalapril.

The method provided herein may additionally produce a water- andsweat-resistant transdermal drug delivery system that comprises a patchthat is occlusive to one or more molecules. These molecules include, butare not limited to, caffeine, aripiprazole, theophylline, dyphilline,pentoxifyline, enprofylline, aminophylline, oxtriphylline, theobromine,propentofylline, xanthinol, doxofylline, pamabrom, lisofylline,ganciclovir, fenethylline, xanthine, uric acid, rolofylline, reproterol,cafedrine and theodrenaline, and any combination thereof.

The method provided herein produces a water- and sweat-resistanttransdermal drug delivery system that has an onset of action within 15minutes of application to the skin of a mammal, and it sustainablydelivers on or more active agents for 8-24 hours. The patch within thetransdermal delivery system produced by the provided method hasexcellent adhesive strength, as shown by a peel rate of about 320mm/min, and allows diffusion of 65% to 100% of the active agent into theskin of a mammal within 8 to 24 hours. The mammal can be an animal or ahuman subject.

Also provided herein is a method of treating seasonal allergic rhinitisin a subject in need thereof, wherein the method comprises applying thewater- and sweat-resistant transdermal drug delivery system comprisingone or more antihistamines to the subject's skin, and maintaining thewater- and sweat-resistant transdermal drug delivery system in contactwith the skin of the subject for 8-24 hours, thereby treating seasonalallergic rhinitis in the subject. Exemplary antihistamines include, butare not limited to, diphenhydramine, desloratidine, cetirizine,loratadine, and any combinations thereof. In some examples, the releaserate of the one or more antihistamines from the patch is 600 μg/cm²/hourduring the first hour of applying the patch. In some examples, therelease rate of the one or more antihistamines from the patch is atleast 100 μg/cm²/hour during the entire time of applying the patch.

Also provided herein is a method of treating seasonal chronic idiopathicurticaria in a subject in need thereof, wherein the method comprisesapplying the water- and sweat-resistant transdermal drug delivery systemprovided herein and comprising one or more antihistamines to thesubject's skin, and maintaining the water- and sweat-resistanttransdermal drug delivery system in contact with the skin of the subjectfor 8-24 hours, thereby treating seasonal chronic idiopathic urticariain the subject. Exemplary antihistamines include, but are not limitedto, diphenhydramine, desloratidine, cetirizine, loratadine, and anycombinations thereof. In some examples, the release rate of the one ormore antihistamines from the patch is 600 μg/cm²/hour during the firsthour of applying the patch. In some examples, the release rate of theone or more antihistamines from the patch is at least 100 μg/cm²/hourduring the entire time of applying the patch.

Also provided herein is a water- and sweat-resistant transdermal drugdelivery system, wherein the patch is a monolithic layer comprising10-30% (w/w) chitosan; 10-40% (w/w) polyvinylpyrrolidone; 10-60%glycerol; 1-20% (w/w) gum Arabic; 10-50% (w/w) lactic acid, and atherapeutically effective amount of one or more antihistamines.Exemplary antihistamines include, but are not limited to,diphenhydramine, desloratidine, cetirizine, loratadine, and anycombinations thereof. In some examples, the release rate of the one ormore antihistamines from the patch is 600 μg/cm²/hour during the firsthour of applying the patch. In some examples, the release rate of theone or more antihistamines from the patch is at least 100 μg/cm²/hourduring the entire time of applying the patch. In some examples, themonolithic layer may further comprise 2-15% (w/w) of one or more fattyacids. The fatty acids include, but are not limited to, tartaric acid,oleic acid, lauric acid, maleic acid, and any combination thereof. Insome examples, the monolithic layer may further comprise 2-15% (w/w) ofone or more essential oils. Essential oils include, but are not limitedto, L-menthol, chuanxiong oil, clove oil, cinnamon oil, turpentine oil,eucalyptus oil, and any combination thereof.

The foregoing and other features of the disclosure will become moreapparent from the following detailed description of several embodiments,which proceeds with reference to the accompanying figures.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the structure of chitosan.

FIG. 2 provides top views and lateral views of transdermal drug deliverysystems provided herein. First from the top of the figure: a top view ofa transdermal drug delivery system provided herein. The transdermal drugdelivery system comprises a drug dispersed in an adhesive polymermatrix, which comprises a layer of chitosan dissolved in lactic acid,glycerol and polyvinyl pyrrolidone (PVP). The liquid matrix is pouredinto the backing layer and solidified by solvent evaporation. The patchis circular, and has a diameter of 4 cm. The backing layer and thematrix are equal in size. The chitosan and polyvinyl pyrrolidone matrixhas a final thickness of approximately 1 mm. Second from the top of thefigure: a top view of a transdermal drug delivery system providedherein. The transdermal drug delivery system comprises a drug dispersedin an adhesive polymer matrix, which comprises a layer of chitosandissolved in lactic acid, glycerol and polyvinyl pyrrolidone (PVP). Theliquid matrix is poured into the backing layer and solidified by solventevaporation. The matrix size is reduced to 3 cm, and then mounted on anadditional backing layer, which has a diameter of 4 cm. The edges of thebacking layer are casted with a medical adhesive to match the thicknessof the matrix. Third from the top of the figure: a lateral view of atransdermal drug delivery system provided herein. The transdermal drugdelivery system comprises a drug dispersed in an adhesive polymermatrix, which comprises a layer of chitosan dissolved in lactic acid,glycerol and polyvinyl pyrrolidone (PVP). The liquid matrix is pouredinto the backing layer and solidified by solvent evaporation. The patchis circular, and has a diameter of 4 cm. The backing layer flushes withthe matrix. The chitosan and polyvinyl pyrrolidone matrix has a finalthickness of approximately 1 mm. Fourth from the top of the figure: alateral view of a transdermal drug delivery system provided herein. Thetransdermal drug delivery system comprises a drug dispersed in anadhesive polymer matrix, which comprises a layer of chitosan dissolvedin lactic acid, glycerol and polyvinyl pyrrolidone (PVP). The liquidmatrix is poured into the backing layer and solidified by solventevaporation. The matrix size is reduced to 3 cm, and then mounted on anadditional backing layer, which has a diameter of 4 cm. The edges of thebacking layer are casted with a medical adhesive to match the thicknessof the matrix.

FIG. 3 shows in vitro diffusion of various drugs through a skinsimulating membrane at air-water interface over time. • Escitalopramoxalate;

4-aminopyridine; ▪ cetirizine dihydrochloride; ♦ aripiprazole. ModifiedFranz Diffusion Cells were filled with 55 ml of phosphate buffer, and askin simulating membrane was placed in each cell at air-water interfaceand secured with a holed cap. The cells were placed into a water bathand the temperature was equilibrated to 38° C. The drug-loaded patch wasgently placed onto the membrane and pressed down lightly. At differenttime points, the drug solution was collected and replaced with freshbuffer, and ultraviolet (UV) absorbance was measured at 200-300 nm withclean quartz cuvettes, using standard curves to determine drugconcentrations and cumulative drug release percentages over time.

FIG. 4 shows the percentage diffusion of 4-aminopyridine through thetransdermal drug delivery system provided herein over time. The patch inthe transdermal drug delivery system consisted of 23% (w/w) glycerol,16% (w/w) gum Arabic, 11% (w/w) medium molecular weight chitosan, and48% (w/w) lactic acid. The patch was prepared by casting the liquidmatrix gel upon a suitable Teflon backing layer and drying for 18 hoursat 55° C. The resulting diffusion profiles were obtained by conductingthe same experiment three times. The patch samples indicate the numberof times that the same experiment was conducted.

FIG. 5 shows the percentage diffusion of 4-aminopyridine through thetransdermal drug delivery system provided herein over time. The patch inthe transdermal drug delivery system consisted of 50% (w/w) glycerol,14% (w/w) PVP, 18% (w/w) medium molecular weight chitosan, and 18% (w/w)lactic acid. The patch was prepared by casting the liquid matrix gelupon a suitable Teflon backing layer and drying for 3 hours at 80° C.The resulting diffusion profiles were obtained by conducting the sameexperiment eight times. The patch samples indicate the number of timesthat the same experiment was conducted.

FIG. 6 shows the percentage diffusion of 4-aminopyridine through thetransdermal drug delivery system provided herein over time. The patch inthe transdermal drug delivery system consisted of 36% (w/w) glycerol,15.3% PVP, 0.7% (w/w) gum Arabic, 9.5% (w/w) medium molecular weightchitosan, and 38.5% (w/w) lactic acid. The patch was prepared by castingthe liquid matrix gel upon a suitable Teflon backing layer and dryingfor 5 hours at 80° C. The resulting diffusion profiles were obtained byconducting the same experiment three times. The patch samples indicatethe number of times that the same experiment was conducted.

FIG. 7 provides a scanning electronic microscopy (SEM) image of thepatch in the transdermal drug delivery system provided herein. Atransdermal patch with desloratadine was formulated by first addingglycerol and lactic acid to a fixed volume of water while stirring themixture at room temperature (25° C.). Chitosan and gum Arabic were nextadded gradually, to facilitate chitosan dissolution and reduceviscosity. PVP was then added to the matrix, and the mixture was stirredfor 2-5 hours. Desloratadine was then added, and the mixture was stirredfor 1-4 hours. The formulation was then casted onto an array of Teflonbackings, and baked at 80° C. for 4-8 hours. The SEM image shows thatthe majority of the desloratadine, the active pharmaceutical ingredient(API) represented by a white powdery substance in the image, dissolvedinto the polymer matrix, represented by the dark background, while somedesloratadine crystals were visible, indicating that the polymer hasbeen saturated with the API.

DETAILED DESCRIPTION

The following explanations of terms and methods are provided to betterdescribe the present disclosure and to guide those of ordinary skill inthe art in the practice of the present disclosure. As used herein,“comprising” means “including” and the singular forms “a” or “an” or“the” include plural references unless the context clearly dictatesotherwise. For example, reference to “comprising a therapeutic agent”includes one or a plurality of such therapeutic agents. The term “or”refers to a single element of stated alternative elements or acombination of two or more elements, unless the context clearlyindicates otherwise. For example, the phrase “A or B” refers to A, B, ora combination of both A and B. Furthermore, the various elements,features and steps discussed herein, as well as other known equivalentsfor each such element, feature or step, can be mixed and matched by oneof ordinary skill in this art to perform methods in accordance withprinciples described herein. Among the various elements, features, andsteps some will be specifically included and others specificallyexcluded in particular examples.

Unless explained otherwise, all technical and scientific terms usedherein have the same meaning as commonly understood to one of ordinaryskill in the art to which this disclosure belongs. Although methods andmaterials similar or equivalent to those described herein can be used inthe practice or testing of the present disclosure, suitable methods andmaterials are described below. The materials, methods, and examples areillustrative only and not intended to be limiting. All references citedherein are incorporated by reference in their entirety.

In some examples, the numbers expressing quantities of ingredients,properties such as molecular weight, reaction conditions, and so forth,used to describe and claim certain embodiments are to be understood asbeing modified in some instances by the term “about” or “approximately.”For example, “about” or “approximately” can indicate +/−20% variation ofthe value it describes. Accordingly, in some embodiments, the numericalparameters set forth herein are approximations that can vary dependingupon the desired properties for a particular embodiment. Notwithstandingthat the numerical ranges and parameters setting forth the broad scopeof some examples are approximations, the numerical values set forth inthe specific examples are reported as precisely as practicable. Therecitation of ranges of values herein is merely intended to serve as ashorthand method of referring individually to each separate valuefalling within the range.

To facilitate review of the various embodiments of this disclosure, thefollowing explanations of specific terms are provided:

Administer: To provide or give a subject an active agent, such as anantihistamine, by an effective route. Administration can be systemic orlocal. Exemplary routes of administration include, but are not limitedto, topical, transdermal, buccal, vaginal, intranasal, rectal,inhalation, ocular, otic, enteral (e.g., oral, sublingual, buccal,rectal) and parenteral (e.g., injections (such as subcutaneous,intramuscular, intradermal, intraperitoneal, intratumoral, andintravenous) routes.

Air-Liquid Interface (ALI): A culture of cells in which the basalsurface of the cells is in contact with liquid culture medium, whereasthe apical surface is exposed to air. A common approach is to seed cellsonto the permeable membrane of a cell culture insert, which is initiallysupplied with culture medium to both the apical and basal compartments.Once confluence is reached, the cells are subjected to ‘air-lift’, wherethe medium is supplied only to the basal chamber. This configurationmimics the conditions found in the human airway on the skin.

Analgesic: A drug or a group of drugs used to provide relief from pain.Analgesic drugs act in various ways on the peripheral and centralnervous systems, and are distinct from anesthetics, which reversiblyeliminate sensation.

Analog: A compound having a structure similar to another, but differingfrom it, for example, in one or more atoms, functional groups, orsubstructure.

Anesthetic agent: An active agent that causes reduction or loss ofsensation.

Anti-Acne Agent: A chemical and/or biological agent that when topicallyadministered at the site of acne, leads to a visible reduction ofsymptoms associated with the epithelial condition of acne vulgaris.

Anti-Aging Agent: A substance that treats or reduces at least an agingsign of the skin, improves skin appearance, increases thickness of oneor more layers of the skin, improves skin elasticity, resiliency orfirmness, improves skin hydration or moisturization, conceals or reducesthe appearance of fine lines and/or wrinkles, or improves skin textureor smoothness.

Antibiotic: A chemical substance capable of treating bacterialinfections by inhibiting the growth of, or by destroying existingcolonies of bacteria and other microorganisms.

Anti-Fungal Agent: An active agent capable of inhibiting the growth ofor destroying fungi.

Anti-Histamine: A drug that inhibits the action of histamine in the bodyby blocking the receptors of histamine. Exemplary anti-histaminesinclude, but are not limited to, Diphenhydramine, Desloratidine andLoratidine, which are tricyclic H1 antihistamines used to treatallergies effective in doses from about 2 mg to about 10 mg, andCetirizine, which is a second generation antihistamine used for thetreatment of hay fever, allergies, angioedema and hives, effective indoses from about 2 mg to about 10 mg.

Anti-inflammatory agent: An active agent that reduces inflammation andswelling.

Anti-Oxidant: An active agent that inhibits oxidation or reactionspromoted by oxygen or peroxides.

Anti-Protozoal Agent: An active agent capable of inhibiting the growthof or destroying protozoa microorganisms.

Antipruritic Agent: An active agent that reduces, eliminates or preventsitching.

Anti-Viral Agent: An active agent that inhibits the replication of ordestroys viruses.

Bioadhesive: A polymer that exhibits a pressure-sensitive character ofadhesion toward highly hydrated biological surfaces such as the hydratedskin. Exemplary bioadhesive polymers include chitosan, polycarbophil(polycyclic acid cross-linked with divinyl glycol, carbopol/carbomer(carboxy polymethylene), hydroxypropylmethyl cellulose HPMC (cellulose2-hydroxypropylmethyl ether); hydroxyethyl cellulose; xanthan gum; guargum; hydroxypropyl guar; chitosan; sodium alginate; carrageenan; poly(hydroxyl butyrate), poly (e-caprolactone) and copolymers; and poly(ortho esters).

Chemotherapeutic agent or Chemotherapy: A chemical agent withtherapeutic usefulness in the treatment of diseases characterized byabnormal cell growth. Such diseases include tumors, neoplasms, andcancer. In one example, a chemotherapeutic agent is a radioactivecompound. In one example, a chemotherapeutic agent is a biologic, suchas a monoclonal antibody. In some examples, a subject treated with anactive agent using the disclosed methods, is, will be, or was previouslytreated with chemotherapy. Exemplary chemotherapeutic agents areprovided in Slapak and Kufe, Principles of Cancer Therapy, Chapter 86 inHarrison's Principles of Internal Medicine, 14th edition; Perry et al.,Chemotherapy, Ch. 17 in Abeloff, Clinical Oncology 2nd ed., 2000Churchill Livingstone, Inc; Baltzer and Berkery. (eds): Oncology PocketGuide to Chemotherapy, 2nd ed. St. Louis, Mosby-Year Book, 1995; FischerKnobf, and Durivage (eds): The Cancer Chemotherapy Handbook, 4th ed. St.Louis, Mosby-Year Book, 1993).

Contacting: Placement in direct physical association; includes both insolid and liquid form. Contacting can occur in vitro with isolated cells(for example in a tissue culture dish or other vessel) or in vivo byadministering an active agent to a subject.

Control: A reference standard. In some examples, a control is a knownvalue or range of values, such as one indicative of a non-anemic or ananemic subject. In some examples, a control is a value or range ofvalues, indicating a response in the absence of a therapeutic agent.

Crosslinked: A composition containing intramolecular and/orintermolecular crosslinks, whether arising through covalent ornon-covalent bonding. “Non-covalent” bonding includes both hydrogenbonding and electrostatic (ionic) bonding.

Drug or Active Agent: A chemical substance or compound that induces adesired pharmacological or physiological effect, and includes agentsthat are therapeutically effective, prophylactically effective, orcosmeceutically effective. The terms also encompass pharmaceuticallyacceptable, pharmacologically active derivatives and analogs of thoseactive agents specifically mentioned herein, including, but not limitedto, salts, esters, amides, prodrugs, active metabolites, inclusioncomplexes, analogs, and the like. Suitable active agents that may beincorporated into the transdermal drug delivery systems provided hereinand delivered transdermally include, but are not limited to, adrenergicagents; adrenocortical steroids; adrenocortical suppressants; alcoholdeterrents; aldosterone antagonists; amino acids; ammonia detoxicants;anabolic agents; analeptic agents; analgesic agents; androgenic agents;anesthetic agents; anorectic compounds; anorexic agents; antagonists;anterior pituitary activators and anterior pituitary suppressants;anti-acne agents; anti-adrenergic agents; anti-allergic agents;anti-amebic agents; anti-androgen agents; anti-anemic agents;anti-anginal agents; anti-anxiety agents; anti-arthritic agents;anti-asthmatic agents and other respiratory drugs; anti-atheroscleroticagents; anti-bacterial agents; anti-cancer agents, includingantineoplastic drugs, and anti-cancer supplementary potentiating agents;anticholinergics; anticholelithogenic agents; anti-coagulants;anti-coccidal agents; anti-convulsants; anti-depressants; anti-diabeticagents; anti-diarrheals; anti-diuretics; antidotes; anti-dyskineticsagents; anti-emetic agents; anti-epileptic agents; anti-estrogen agents;anti-fibrinolytic agents; anti-fungal agents; anti-glaucoma agents;antihelminthics; anti-hemophilic agents; anti-hemophilic Factor;anti-hemorrhagic agents; antihistamines; anti-hyperlipidemic agents;anti-hyperlipoproteinemic agents; antihypertensive agents;anti-hypotensives; anti-infective agents such as antibiotics andantiviral agents; anti-inflammatory agents, both steroidal andnon-steroidal; anti-keratinizing agents; anti-malarial agents;antimicrobial agents; anti-migraine agents; anti-mitotic agents;anti-mycotic agents; antinauseants; antineoplastic agents;anti-neutropenic agents; anti-obsessional agents; anti-parasitic agents;antiparkinsonism drugs; anti-pneumocystic agents; anti-proliferativeagents; anti-prostatic hypertrophy drugs; anti-protozoal agents;antipruritics; anti-psoriatic agents; antipsychotics; antipyretics;antispasmodics; anti-rheumatic agents; anti-schistosomal agents;anti-seborrheic agents; anti-spasmodic agents; anti-tartar andanti-calculus agents; anti-thrombotic agents; anti-tubercular agents;antitussive agents; anti-ulcerative agents; anti-urolithic agents;antiviral agents; GERD medications, anxiolytics; appetite suppressants;attention deficit disorder (ADD) and attention deficit hyperactivitydisorder (ADHD) drugs; bacteriostatic and bactericidal agents; benignprostatic hyperplasia therapy agents; blood glucose regulators; boneresorption inhibitors; bronchodilators; carbonic anhydrase inhibitors;cardiovascular preparations including anti-anginal agents,anti-arrhythmic agents, beta-blockers, calcium channel blockers, cardiacdepressants, cardiovascular agents, cardioprotectants, and cardiotonicagents; central nervous system (CNS) agents; central nervous systemstimulants; choleretic agents; cholinergic agents; cholinergic agonists;cholinesterase deactivators; coccidiostat agents; cognition adjuvantsand cognition enhancers; cough and cold preparations, includingdecongestants; depressants; diagnostic aids; diuretics; dopaminergicagents; ectoparasiticides; emetic agents; enzymes which inhibit theformation of plaque, calculus or dental caries; enzyme inhibitors;estrogens; fibrinolytic agents; fluoride anticavity/antidecay agents;free oxygen radical scavengers; gastrointestinal motility agents;genetic materials; glucocorticoids; gonad-stimulating principles; hairgrowth stimulants; hemostatic agents; herbal remedies; histamine H2receptor antagonists; hormones; hormonolytics; hypnotics;hypocholesterolemic agents; hypoglycemic agents; hypolipidemic agents;hypotensive agents; HMGCoA reductase inhibitors; immunizing agents;immunomodulators; immunoregulators; immunostimulants;immunosuppressants; impotence therapy adjuncts; inhibitors; keratolyticagents; leukotriene inhibitors; LHRH agonists; liver disordertreatments; luteolysin agents; memory adjuvants; mental performanceenhancers; metal chelators such as ethylenediaminetetraacetic acid,tetrasodium salt; mitotic inhibitors; mood regulators; mucolytics;mucosal protective agents; muscle relaxants; mydriatic agents; narcoticantagonists; nasal decongestants; neuroleptic agents; neuromuscularblocking agents; neuroprotective agents; nicotine; NMDA antagonists;non-hormonal sterol derivatives; nutritional agents, such as vitamins,essential amino acids and fatty acids; ophthalmic drugs such asantiglaucoma agents; oxytocic agents; pain relieving agents;parasympatholytics; peptide drugs; plasminogen activators; plateletactivating factor antagonists; platelet aggregation inhibitors;post-stroke and post-head trauma treatments; potentiators; progestins;prostaglandins; prostate growth inhibitors; proteolytic enzymes as woundcleansing agents; prothyrotropin agents; psychostimulants; psychotropicagents; radioactive agents; regulators; relaxants; repartitioningagents; scabicides; sclerosing agents; sedatives; sedative-hypnoticagents; selective adenosine A1 antagonists; serotonin antagonists;serotonin inhibitors; serotonin receptor antagonists; steroids,including progestogens, estrogens, corticosteroids, androgens andanabolic agents; smoking cessation agents; stimulants; suppressants;sympathomimetics; synergists; thyroid hormones; thyroid inhibitors;thyromimetic agents; tranquilizers; tooth desensitizing agents; toothwhitening agents such as peroxides, metal chlorites, perborates,percarbonates, peroxyacids, and combinations thereof; unstable anginaagents; uricosuric agents; vasoconstrictors; vasodilators includinggeneral coronary, peripheral and cerebral; vulnerary agents; woundhealing agents; xanthine oxidase inhibitors; and the like.

Effective amount or Therapeutically effective amount: The amount of atherapeutic agent (alone or with one or more other therapeutic agents)sufficient to induce a desired response, such as to prevent, treat,reduce and/or ameliorate the symptoms and/or underlying causes of any ofa disorder or disease, or to increase the number of cells, such as toincrease the proliferation of cells, including stem cells. In oneexample, an “effective amount” is sufficient to reduce or eliminate asymptom of a disease, such as a sign or symptom of allergic rhinitis. Inanother example, an effective amount is an amount sufficient to overcomethe disease itself. In a further example, an effective amount of atherapeutic agent, such as an antihistamine, is an amount that producesa statistically significant decrease in the symptoms of a disease, suchas allergic rhinitis, as compared to a control, such as a culture orsubject not treated with an antihistamine or treated with vehicle alone.

The condition or disease, such as allergic rhinitis or urticaria, doesnot need to be completely inhibited for the pharmaceutical preparationto be effective. Treatment can include slowing the progression of thedisease temporarily, but can also include halting or reversing theprogression of the disease permanently. For example, a pharmaceuticalpreparation can alleviate one or more signs or symptoms associated withallergic rhinitis or urticaria by decreasing the symptoms by at least20%, at least 50%, at least 60%, at least 70%, at least 80%, at least90%, at least 95%, at least 98%, even at least 100%, as compared to thesymptoms in the absence of the pharmaceutical preparation.

Effective amounts of a therapeutic agent, alone or with one or moreother therapeutic agents, can be determined in many different ways, suchas assaying for a reduction in of one or more signs or symptomsassociated with the condition, such as allergic rhinitis or urticaria,in the subject or measuring the level of one or more moleculesassociated with the condition to be treated. Effective amounts also canbe determined through various in vitro, in vivo or in situ assays,including the assays described herein.

Emulsifying Agents: Surfactants that reduce the interfacial tensionbetween oil and water, minimizing the surface energy through formationof globules. Examples include, but are not limited to, glycerylmonostearate, methylcellulose, sodium lauryl sulfate, sodium oleate,sorbitan monopalmitate, sorbitan monostearate, sorbitan tristrearate,tragacanth, triethanolamine oleate, polyethylene sorbitan monolaurate,poloxamer, and any combination thereof.

Hydrogel: A water-swellable polymeric matrix that can absorb asubstantial amount of water to form elastic gels. The matrix is athree-dimensional network of macromolecules held together by covalent ornon-covalent crosslinks. Upon placement in an aqueous environment, dryhydrogels swell to the extent allowed by the degree of cross-linking.

Hydrogel Composition: A composition that either contains a hydrogel oris entirely composed of a hydrogel. Thus, “hydrogel compositions”encompass not only hydrogels per se but also compositions that comprisea hydrogel and one or more non-hydrogel components or compositions,e.g., hydrocolloids, which contain a hydrophilic component (which maycontain or be a hydrogel) distributed in a hydrophobic phase.

Hydrophilic: A polymer, substance or compound capable of absorbing morethan 10%/w of water at 100% relative humidity (rh).

Hydrophobic: A polymer, substance or compound capable of absorbing nomore than 1%/w of water at 100% relative humidity (rh).

Hygroscopic: A polymer, substance or compound capable of absorbing morethan 20 wt % of water at 100% relative humidity (rh).

Immune Response: The reaction to and interaction with substancesinterpreted by the body as not-self. The immune response depends on afunctioning thymus and the conversion of stem cells to B and Tlymphocytes. These lymphocytes contribute to antibody production,cellular immunity, and immunologic memory. Pathologic conditionsassociated with an abnormal immune response (immunopathy) may resultfrom immuno-depression, excessive production of gamma globulins,overreaction to antigens of extrinsic origin, or abnormal response ofthe body to its own cells and tissues. Factors that may cause orcontribute to suppression of the immune response include (1) congenitalabsence of the thymus or of the stem cells that are precursors of B andT lymphocytes; (2) malnutrition, in which there is a deficiency of thespecific nutrients essential to the life of antibody-synthesizing cells;(3) cancer, viral infections, and extensive burns, all of whichoverburden the immune response mechanisms and rapidly deplete the supplyof antigen-specific antibody; (4) certain drugs, including alcohol andheroin, some antibiotics, antipsychotics, and the antineoplastics usedin the treatment of cancer. Overproduction of gamma globulins ismanifested by an excessive proliferation of plasma cells (multiplemyeloma). Hypersensitivity is the result of an overreaction tosubstances entering the body.

Inhibiting a disease or condition: Reducing, slowing, or even stoppingthe development of a disease or condition, for example, in a subject whois at risk for a disease or who has a particular disease, such asallergic rhinitis or urticaria.

Keratolytic Agent: An agent that that thins or softens the skin.Exemplary keratolytic agents include urea, lactic acid, allantoin,benzoyl peroxide, salicyclic acid, sulfur, tretinoin, fluorouracil,trichloroacetic acid, and glycolic acid.

Lipophilic: A substance or compound that has an affinity for a non-polarenvironment compared to a polar or aqueous environment.

Localized administration: The administration of a therapeutic agent in aparticular location in the body.

Matrix: A three dimensional network of polymeric fibers that containspores. The structural parameters of the pores, including the pore size,porosity, pore interconnectivity/tortuosity and surface area, affect howactive agents dispersed in the matrix move in and out of the matrix.

Patch: A topical patch may be in multiple forms, including single andmultilayer drug-in-adhesive forms, matrix forms, and reservoir forms,and has a finite size and shape. Thus, the application area on the skinis determined by the dimensions of the patch, rather than by thedimensions of the affected site.

Permeation Enhancer: A natural or synthetic molecule that facilitatesthe transport of co-administered active agents across biologicalmembranes.

pH Modifier: A molecule or buffer used to achieve desired pH control ina formulation. Exemplary pH modifiers include acids (e.g., acetic acid,adipic acid, carbonic acid, citric acid, fumaric acid, phosphoric acid,sorbic acid, succinic acid, tartaric acid, basic pH modifiers (e.g.,magnesium oxide, tribasic potassium phosphate), and pharmaceuticallyacceptable salts thereof.

Pharmaceutically acceptable carriers: The pharmaceutically acceptablecarriers useful in this disclosure are conventional. Remington'sPharmaceutical Sciences, by E. W. Martin, Mack Publishing Co., Easton,Pa., 19th Edition (1995), describes compositions and formulationssuitable for pharmaceutical delivery of the compositions hereindisclosed (such as antihistamines). For example therapeutic agents canbe administered in the presence of one or more pharmaceuticallyacceptable carriers, including a non-natural or natural pharmaceuticallyacceptable carrier molecule.

The nature of the carrier can depend on the particular mode ofadministration being employed. For instance, transdermal formulationsusually include pharmaceutically and physiologically acceptable fluidssuch as water, physiological saline, balanced salt solutions, aqueousdextrose, glycerol or the like as a vehicle. In addition tobiologically-neutral carriers, pharmaceutical compositions to beadministered can contain minor amounts of non-toxic auxiliarysubstances, such as wetting or emulsifying agents, preservatives, and pHbuffering agents and the like, for example sodium acetate or sorbitanmonolaurate. Embodiments of other pharmaceutical compositions can beprepared with conventional pharmaceutically acceptable carriers,adjuvants, and counter-ions, as would be known to those of skill in theart.

Plasticizer: A material that, when added to a polymer, imparts anincrease in flexibility, workability, and other properties to thefinished product. Exemplary plasticizers include, but are not limitedto, glycerol, sorbitol, polyethylene glycol, polypropylene glycol,polyethylene-propylene glycol, and any combination thereof.

Polymer: Includes homopolymers, linear and branched polymer structures,crosslinked polymers, copolymers (which may or may not be crosslinked),block copolymers, alternating copolymers, random copolymers, and thelike. Oligomers are polymers having a molecular weight below about 1000Da.

Polyvinylpyrrolidone or PVP: A synthetic polymer consisting of linear1-vinyl-2-pyrrolidinone groups; it is produced commercially as a seriesof products having mean molecular weights ranging from about 10,000 toabout 700,000. The viscosity of solutions containing 10% or less PVP isessentially the same as that of water; solutions more concentrated than10% become more viscous, depending on the concentration and molecularweight of the polymer used.

Pressure sensitive adhesive (PSA): A polymer material, which forms astrong adhesive bond to any surface with application of very slightexternal pressure over a short period of time (e.g., 1-5 seconds).

Scanning Electron Microscope (SEM): a technique that scans a focusedelectron beam over a surface to create an image. The electrons in thebeam interact with the sample, producing various signals that can beused to obtain information about the surface topography and composition.The electron beam is scanned in a raster scan pattern, and the beam'sposition is combined with the detected signal to produce an image. SEMcan achieve resolution better than 1 nanometer. Specimens can beobserved in high vacuum in conventional SEM, or in low vacuum or wetconditions in variable pressure or environmental SEM, and at a widerange of cryogenic or elevated temperatures with specializedinstruments.

Skin: The largest organ in the body consisting of several layers. Theskin plays an important role in biologic homeostasis, and is comprisedof the epidermis and the dermis. The epidermis, which is composed ofseveral layers beginning with the stratum corneum, is the outermostlayer of the skin, and the deep dermis is the innermost skin layer. Theskin has multiple functions, including thermal regulation, metabolicfunction (vitamin D metabolism), and immune functions. In humans, theusual thickness of the skin is 1-2 mm, although in some areas the skinmay be more than 5 mm thick.

The epidermis provides the body's buffer zone against the environmentand protection from trauma, excludes toxins and microbial organisms, andconstitutes a semi-permeable membrane. The stratum corneum is anavascular, multilayer structure that functions as a barrier to theenvironment and prevents trans-epidermal water loss. Below the stratumcorneum are the stratum lucidum, stratum granulosum, stratumgerminativum, and stratum basale, each containing living cells withspecialized functions. Dermal appendages, which include hair follicles,sebaceous and sweat glands, fingernails, and toenails, originate in theepidermis and protrude into the dermis hair follicles. The sebaceousglands are responsible for secretions that lubricate the skin, and sweatgland secretions control skin pH to prevent dermal infections. The sweatglands, dermal blood vessels, and small muscles control temperature onthe surface of the body. Nerve endings in the skin include receptors forpain, touch, heat, and cold. The basement membrane separates andconnects the epidermis and dermis. The dermis is a vascular structurethat supports and nourishes the epidermis. In addition, there aresensory nerve endings in the dermis that transmit signals regardingpain, pressure, heat, and cold. The superficial dermis consists ofextracellular matrix (collagen, elastin, and ground substances) andcontains blood vessels, lymphatics, epithelial cells, connective tissue,muscle, fat, and nerve tissue. The vascular supply of the dermis isresponsible for nourishing the epidermis and regulating bodytemperature. Fibroblasts are responsible for producing the collagen andelastin components of the skin, which give the skin its turgor.Fibronectin and hyaluronic acid are secreted by the fibroblasts. Thedeep dermis is located over the subcutaneous fat; it contains largernetworks of blood vessels and collagen fibers to provide tensilestrength. It also consists of fibroelastic connective tissue, which iscomposed mainly of collagen.

Skin Simulating Membrane: A semi-permeable membrane used to replicatethe skin in diffusion testing.

Subject: A living multi-cellular vertebrate organism, a category thatincludes human and non-human mammals, as well as birds (such as chickensand turkeys), fish, and reptiles. Exemplary subjects include mammals,such as human and non-human primates, rats, mice, dogs, cats, rabbits,cows, pigs, goats, horses, and the like.

Surface or Body Surface: A surface located on the human body or within abody orifice. Thus, a “body surface” includes, by way of example, skin,teeth, skin or mucosal tissue, including the interior surface of bodycavities that have a mucosal lining.

Tacky: May be quantified using the values obtained in a PKI tackdetermination, a TRBT tack determination, or a PSA tackdetermination/Polyken Probe (Solutia, Inc.). The term “substantiallynontacky” means a hydrogel composition that has a tack value that isless than about 25 g/cm/sec; “slightly tacky” means a hydrogelcomposition that has a tack value in the range of about 25 g/cm/sec toabout 100 g/cm/sec; and “tack” means a hydrogel composition that has atack value of at least 100 g/cm/sec.

Transdermal Drug Delivery System: A system that administer an activeagent to the skin or mucosa of an individual so that the drug passesthrough the skin tissue and into the individual's blood stream. The term“transdermal” may also include “transmucosal” drug administration, i.e.,administration of a drug to the mucosal (e.g., sublingual, buccal,vaginal, rectal, urethral) surface of an individual so that the drugpasses through the mucosal tissue and into the individual's bloodstream. For example, a transdermal drug delivery device may contain amatrix, in which one or more drugs or active agents are dispersed, abacking layer, a rate-controlling membrane, and an adhesive means foraffixing the system to a body surface.

Topical administration: Delivery of an active agent to a body surface,such as, the skin or mucosa, as in, for example, topical drugadministration in the prevention or treatment of various skin disorders,the application of cosmetics (including moisturizers, masks, sunscreens,etc.), and the like. Topical administration, in contrast to transdermaladministration, provides a local rather than a systemic effect.

Under conditions sufficient to: A phrase that is used to describe anyenvironment that permits the desired activity.

Water-Insoluble: A polymer, compound or composition whose solubility inwater is less than 5%/w, less than 3%/w, or less than 1%/w, measured inwater at 20° C.

Water-Swellable: A polymer, substance or compound capable of absorbingan amount of water greater than at least 25%/w of its own weight, orgreater than at least 50%/w, upon immersion in an aqueous medium.

Transdermal Drug Delivery System

A transdermal drug delivery system is disclosed. The disclosedtransdermal drug delivery system comprises a patch having a diameterbetween 1 and 8 cm in length and a surface area between 4 and 7.5 cm².The small size of the patch enables the water- and sweat-resistanttransdermal drug delivery system to provide a large surface-to-volumeratio, such that large amounts of drugs may be delivered through theskin into the blood stream, and the surface area of the skin requiredfor administration is minimized. The transdermal delivery system has anonset of action within 5 to 15 minutes, and allows about 65% to about100% of one or more drugs to diffuse into the skin of a mammal within 8to 24 hours.

The transdermal drug delivery system provided herein is water- andsweat-resistant. The patch does not come off upon contact with water(e.g. sweating, showering). Rather, the hydrophilicity of the patchleads to higher adhesion onto the skin when wet. Additionally, water maydecrease the viscosity of the patch, allowing it to better flow intopockets in the skin and to increase the surface area of adhesion.

The transdermal drug delivery system disclosed herein is alsoparticularly suitable for use on sensitive skin. The patch comprises amonolithic layer of about 1 to 5 mm in width, wherein the monolithiclayer comprises 10-30% (w/w) of a bioadhesive polymer; 10-40% (w/w) of afilm-forming agent; 10-60% (w/w) of a plasticizer; 1-20% (w/w) of anaturally occurring polysaccharide; 10-50% (w/w) of a keratolytic agent;and 1-60% (w/w) of one or more active agents. The particular choice ofthe patch components and their ratio ensures that the patch causes noirritation to the skin, and no redness or swelling even after prolongedperiods of use. Therefore, the disclosed transdermal drug deliverysystem is particular suitable for use in subjects with sensitive skin,such as elderly and pediatric populations.

In some examples, the bioadhesive polymer may include chitosan,hydroxypropylmethyl cellulose, hydroxyethyl cellulose, xanthan gum, guargum, sodium alginate, or a combination thereof. In some examples, thefilm-forming agent may include polyvinyl alcohol, polyvinyl pyrrolidone,carrageenan, gelatin, dextrin, polyethylene oxide, guar gum, xanthangum, or a combination thereof. In some additional examples, theplasticizer may include glycerol, sorbitol, polyethylene glycol,polypropylene glycol, polyethylene-propylene glycol, or a combinationthereof. In some other examples, the naturally occurring polysaccharidemay include agar, alginate, chitin, glucomannan, gellan gum, gelatin,gum guar, gum Arabic, locust bean gum, pectin, xanthan, or a combinationthereof. In some examples, the keratolytic agent may include urea,lactic acid, allantoin, benzoyl peroxide, salicyclic acid, or acombination thereof.

In some examples, the patch comprises chitosan (10-30% w/w),polyvinylpyrrolidone (PVP) (10-40% w/w), glycerol (10-60% w/w), gumArabic (less than 20% w/w), and lactic acid (10-50% w/w). Without beingbound to any theory, chitosan increases viscosity and decreases skinirritation; PVP increases cohesiveness and water resistance, anddecreases adhesiveness; glycerol increases adhesiveness and reducescohesion and rigidity; gum Arabic increases adhesion and reducescohesion; and lactic acid increases homogeneity and decreases skinirritation and cohesion. Moreover, the patch possesses great adhesivestrength, with a peel rate of approximately 320 mm/min.

The disclosed transdermal drug delivery system can deliver differentsmall molecules with a wide variety of functional groups including, butnot limited to, aliphatic chains, aromatic rings, pyridine rings, purinerings, imidazole rings, halogenated aromatic rings, alcohols, ethers,carboxylic acids, aldehydes, ketones, esters, primary amines, secondaryamines, and tertiary amines, primary amides, secondary amides andtertiary amides, thiols, sulfines, sulfones, sulfonamides, thioamides,sulfonoesters and thioesters among others.

The patch is capable of holding and delivering a number of drugsincluding, but not limited to, diphenhydramine, desloratadine,cetirizine, dalfampridine, amitriptyline, etoricoxib, glicazide,lisinopril, tramadol, propranolol, ondansetron, diphenhydramine,fluoxetine, duloxetine, levodopa, loratadine, orlistat, venlaflaxine,pioglitzazone, fingolimod, escitalopram, carbidopa, alprazolam,clonazepam, modafinil, armodafinil, dextroamphetamine, fluorenol,aniracetam, coluracetam, fasoracetam, nefiracetam, oxiracetam,phenylpiracetam, piracetam, pramiracetam, adrafinil, alpha-GPC, cholinebitartrate, citicoline, creatine, tyrosine, bromantane, cotinine,L-theanine, N-acetylcysteine, noopept, prolintane, tianeptine,buproprion, citalopram, sertraline, trazodone, mirtazapine, paroxetine,amitryptyline, lamotrigine, nortriptyline, quetiapine, tramadol,doxepin, olanzapine, risperidone, imipramine, lithium, simvastatin,pravastatin, lovastatin, rosuvastatin, prednisone, dimethylx fumarate,mitoxantrone, natalizumab, teriflunomide, dexamethasone, prednisolone,valacyclovir, azathioprine, cyclophosphamide, mycophenolate,haloperidole, esomeprazole, rivarocaban, oxycodone, valsartan,memantine, quetiapine, sevelamer, budenoside, hydrocodone, doxycycline,eszopiclone, fenofibrate, metoprolol, valproate, omeprazole, metformin,amlodipine, losartan, zolpidem, hydrochlorothiazide, pantoprazole,amoxicillin, tamsulosin, fluticasone, carvedilol, warfarin, meloxicam,clopidogrel, atenolol, tadalafill, salbutamol, albuterol,cyclobenzaprine, capsaicin, celecoxib, baclofen, acrivastine,pseudoephedrine, loxapine, riociguat, lubiprostone, prostacyclin,benzphetamine, bortezomib, busulfan, cinacalet, nadolol, fenoldopam,cyproheptadine, cysteamine, decitabine, darifenacin, dacogen,desvenlaxafine, amfepramone, quazepam, famotidine, prasugrel,eletriptan, eplernone, perphenazine, melphalan, exemestane, ezetimibe,penciclovir, fenolodpam, fesoterodine, fluoricortisone, hydrocodone,frovatriptan, tigecycline, ziprasidone, glipizide, miglitol,guanethidine, guanfacine, camptothecin, hyoscyamine, ibrutinib,ibutilide and iloprost.

In some examples, the active agent or drug is one or more ofDiphenhydramine, Desloratadine, Cetirizine, Loratadine, Trihexyphenidyl,Asenapine, Prostacyclin, Buspirone, Butorphanol, Captopril, Carbidopa,Albuterol, Naltrexonelvabradine, Dexamethasone, Phenylephrine,Fluocinolone acetonide, Dexlansoprazole, Furosemide, Isradipine,Venlafaxine, and Enalapril. Table 1 below shows the structure of some ofthe drugs that may be transdermally delivered by the transdermal drugdelivery system provided herein.

TABLE 1 Molecular Weight Trade Medical Drug Name Molecular Structure(Da) Name Purpose Cetirizine dihydrochloride

461.81 Zyrtec ®, others Allergies Desloratadine

310.82 Clarinex ®, Aerius ®, others Allergies 4-Aminopyridine

94.11 Ampyra ®, Fampyra ®, others Multiple sclerosis Aripiprazole

448.39 Abilify ®, others Schizophrenia, bipolar disorder EscitalopramOxalate

414.43 Lexapro ®, others Depression, anxiety

The active agents or drugs may be released from the polymeric matrix inthe patch by diffusion. The release may be a controlled release, adelayed release, or a sustained release. The concentration of the one ormore active agents or drugs in the patch is at least 1% w/w of thecomposition, at least 2% w/w of the composition, at least 3% w/w of thecomposition, at least 4% w/w of the composition, at least 5% w/w of thecomposition, at least 6% w/w of the composition, at least 7% w/w of thecomposition, at least 8% w/w of the composition, at least 9% w/w of thecomposition, at least 10% w/w of the composition; at least 11% w/w ofthe composition; at least 12% w/w of the composition; at least 13% w/wof the composition; at least 14% w/w of the composition; at least 15%w/w of the composition; at least 16% w/w of the composition; at least17% w/w of the composition; at least 18% w/w of the composition; atleast 19% w/w of the composition; at least 20% w/w of the composition,at least 30% w/w of the composition, at least 40% w/w of thecomposition, at least 50% w/w of the composition, or at least 60% w/w ofthe composition.

The content of the one or more active agents or drugs transdermallydelivered to the skin and their permeation/flux into the skin may bemeasured as a function of time. In some examples, the flux is determinedusing an artificial skin simulating membrane or human cadaver skinattached to a Franz diffusion cell, as described in the examples.

Optionally, the disclosed transdermal drug delivery system may comprisea backing layer and trimmed to a desired size. Suitable materials forthe backing layer include, but are not limited to, Teflon, metal foils,metalized polyfoils, composite foils or films containing polyester, suchas polyester terephthalate, polyester or aluminized polyester,polytetrafluoroethylene, polyether block amide copolymers, polyethylenemethyl methacrylate block copolymers, polyurethanes, polyvinylidenechloride, nylon, silicone elastomers, rubber-based polyisobutylene,styrene, styrene-butadiene and styrene-isoprene copolymers,polyethylene, and polypropylene. Additionally, the backing layer mayinclude various foams, such as, but not limited to, polyolefin foams,polyvinyl chloride foams, polyurethane foams, and polyethylene foams.

The backing layer may contain occlusive agents or be substantiallyimpermeable to the components of the patch. In some examples, thetransdermal drug delivery system is occlusive to one or more molecules,including, but not limited to, caffeine, aripiprazole, theophylline,dyphilline, pentoxifyline, enprofylline, aminophylline, oxtriphylline,theobromine, propentofylline, xanthinol, doxofylline, pamabrom,lisofylline, ganciclovir, fenethylline, xanthine, uric acid,rolofylline, reproterol, cafedrine and theodrenaline, and anycombination thereof.

The transdermal drug delivery system provided herein may be applied tothe skin, deliver one or more drugs, and be left on the skin for atleast 1 hour, at least 2 hours, at least 3 hours, at least 4 hours, atleast 5 hours, at least 6 hours, at least 7 hours, at least 8, at least9, at least 10, at least 11, at least 12 hours, at least 13 hours, atleast 14 hours, at least 15 hours, at least 16 hours, at least 17 hours,at least 18 hours, at least 19 hours, at least 20 hours, at least 21hours, at least 22 hours, at least 23 hours, at least 24 hours, at least25 hours, at least 26 hours, at least 27 hours, at least 28 hours, atleast 29 hours, at least 30 hours, at least 31 hours, at least 32 hours,at least 33 hours, at least 34 hours, at least 35 hours, at least 36hours, at least 37 hours, at least 38 hours, at least 39 hours, at least40 hours, at least 41 hours, at least 42 hours, at least 43 hours, atleast 44 hours, at least 45 hours, at least 46 hours, at least 47 hours,at least 48 hours, at least 49 hours, at least 50 hours, at least 51hours, at least 52 hours, at least 53 hours, at least 54 hours, at least55 hours, at least 56 hours, at least 57 hours, at least 58 hours, atleast 59 hours, at least 60 hours, at least 61 hours, at least 62 hours,at least 63 hours, at least 64 hours, at least 65 hours, at least 66hours, at least 67 hours, at least 68 hours, at least 69 hours, at least70 hours, at least 71 hours, at least 72 hours, at least 73 hours, atleast 74 hours, at least 75 hours, at least 76 hours, at least 77 hours,at least 78 hours, at least 79 hours, at least 80 hours, at least 81hours, at least 82 hours, at least 83 hours, at least 84 hours, at least85 hours, at least 86 hours, at least 87 hours, at least 88 hours, atleast 89 hours, at least 90 hours, at least 91 hours, at least 92 hours,at least 93 hours, at least 94 hours, at least 95 hours, at least 96hours, at least 97 hours, at least 98 hours, at least 99 hours, at least100 hours, at least 110 hours, or at least 120 hours before it isremoved.

The disclosed transdermal drug delivery system may further comprise apenetration enhancer. Non-limiting examples of penetration enhancersinclude glycerol monolaurate (GML), lecithin, or a vegetable oil, forexample, safflower oil, cottonseed oil and corn oil.

The disclosed transdermal drug delivery system may further comprise ananti-oxidant. Exemplary anti-oxidants include, but are not limited to,ascorbic acid (vitamin C) and its salts, ascorbyl esters of fatty acids,ascorbic acid derivatives (e.g., magnesium ascorbyl phosphate, sodiumascorbyl phosphate, ascorbyl sorbate), tocopherol (vitamin E),tocopherol sorbate, tocopherol acetate, other esters of tocopherol,butylated hydroxy benzoic acids and their salts, bioflavonoids,curcumin, lysine, methionine, proline, superoxide dismutase, silymarin,tea extracts, grape extracts, melanin, and rosemary extracts. Theantioxidant may be present at a concentration from 0.1% to 10% w/w ofthe patch.

The patch may further comprise auxiliary agents, e.g., lubricants,preservatives, stabilizers, wetting agents, emulsifiers, salts forinfluencing osmotic pressure, buffers, colorants, flavorants and/orfragrances and the like which do not deleteriously react with the activecompounds.

Thus, the water- and sweat-resistant transdermal drug delivery systemprovided herein provides a dosage form that achieves quick deliverythrough the skin into the blood stream, reduces common side effects andimproves patient compliance.

Method of Making the Disclosed Transdermal Drug Delivery System

Also provided herein is a method of making a water- and sweat-resistanttransdermal drug delivery system. The method comprises first adding afilm-forming agent and a plasticizer to water and stirring the mixtureat room temperature (25° C.); gradually adding a bioadhesive polymer anda naturally occurring polysaccharide and stir the mixture until thebioadhesive polymer is dissolved and viscosity is reduced; then adding afilm-forming agent and a keratolytic agent and stirring for 2-5 hoursuntil an even mixture is obtained; adding one or more active agents andstirring the mixture for 1-4 hours to obtain a formulation; andoptionally casting the formulation onto an array of backing layers andbaking the backing layers at 80° C. for 4-8 hours to obtain a patch witha backing layer.

The bioadhesive polymer may include chitosan, hydroxypropylmethylcellulose, hydroxyethyl cellulose, xanthan gum, guar gum, sodiumalginate, or a combination thereof. The film-forming agent may includepolyvinyl alcohol, polyvinyl pyrrolidone, carrageenan, gelatin, dextrin,polyethylene oxide, guar gum, xanthan gum, or a combination thereof. Insome additional examples, the plasticizer may include glycerol,sorbitol, polyethylene glycol, polypropylene glycol,polyethylene-propylene glycol, or a combination thereof. The naturallyoccurring polysaccharide may include agar, alginate, chitin,glucomannan, gellan gum, gelatin, gum guar, gum Arabic, locust bean gum,pectin, xanthan, or a combination thereof. The keratolytic agent mayinclude urea, lactic acid, allantoin, benzoyl peroxide, salicyclic acid,or a combination thereof. In some examples, the patch comprises 10-30%(w/w) chitosan; 10-40% (w/w) polyvinylpyrrolidone; 10-60% glycerol;1-20% (w/w) gum Arabic; and 10-50% (w/w) lactic acid.

In some examples, the disclosed transdermal drug delivery system maycomprise a backing layer. Suitable materials for the backing layerinclude, but are not limited to, Teflon, metal foils, metalizedpolyfoils, composite foils or films containing polyester, such aspolyester terephthalate, polyester or aluminized polyester,polytetrafluoroethylene, polyether block amide copolymers, polyethylenemethyl methacrylate block copolymers, polyurethanes, polyvinylidenechloride, nylon, silicone elastomers, rubber-based polyisobutylene,styrene, styrene-butadiene and styrene-isoprene copolymers,polyethylene, and polypropylene. Additionally, the backing layer mayinclude various foams, such as, but not limited to, polyolefin foams,polyvinyl chloride foams, polyurethane foams, and polyethylene foams.

In some examples, the provided method may further comprise adding 2-15%(w/w) of one or more fatty acids. The fatty acids include, but are notlimited to, tartaric acid, oleic acid, lauric acid, maleic acid, and anycombination thereof. In some examples, the provided method may furthercomprise adding 2-15% (w/w) of one or more essential oils. Essentialoils include, but are not limited to, L-menthol, chuanxiong oil, cloveoil, cinnamon oil, turpentine oil, eucalyptus oil, and any combinationthereof.

The provided method produces a water- and sweat-resistant transdermaldrug delivery system that may deliver a great variety of active agentsinto the skin. In some example, only one active agent at the time isdelivered into the skin. In other examples, a combination of activeagents is delivered into the skin, either sequentially orcontemporaneously. Examples of active agents include, but are notlimited to, one or more antihistamines, potassium channel blockers,analgesic agents, antidiabetic agents, pain-relief agents,antidepressant agents, antipsychotic agents, anti-Parkinsonian agents,vasodilators, diuretics, calcium channel blockers, anti-acne agents,anti-aging agents, antibiotic agents, antifungal agents, ACE inhibitors,GERD medications, anti-inflammatory agents, opioids, anti-asthma agents,corticosteroids, nicotinic cholinergic receptor agonists, anti-oxidantagents, antiprotozoal agents, antipruritic agents, antiviral agents,chemotherapeutic agents, immunomodulatory agents, keratolytic agents,retinoids, and central nervous system stimulants. Thus, in someexamples, the active agent is on or more of Diphenhydramine,Desloratadine, Cetirizine, Loratadine, Trihexyphenidyl, Asenapine,Prostacyclin, Buspirone, Butorphanol, Captopril, Carbidopa, Albuterol,Naltrexone, Ivabradine, Dexamethasone, Phenylephrine, Fluocinoloneacetonide, Dexlansoprazole, Furosemide, Isradipine, Venlafaxine, andEnalapril.

Exemplary antihistamines include, but are not limited to,Diphenhydramine, Loratadine, Desloratadine, and Cetirizine. Exemplaryantidepressants and anti-anxiety agents include, but are not limited to,Sertraline, Fluoxetine, Paroxetine, Venlaxafine, Duloxetine,Escitalopram Oxalate, Alprazolam, and Lorazepam. Exemplary ADHDmedications include, but are not limited to, amphetamine aspartate,dextroamphetamine, methylphenidate hydrochloride, dexmethylphenidatehydrochloride, and amitriptyline. Exemplary Anti-Parkinson's medicationsinclude, but are not limited to, Levodopa, Carbidopa, Ropinirole,Pramipexole, Rotigotine, Apomorphine, Selegine Hydrochloride,Rasagiline, and Benztropine. Exemplary Multiple Sclerosis Medicationsinclude, but are not limited to, Teriflunomide, Dalfampridine, DimethylFumarate, Natalizumab, Fingolimod, and Glatiramer Acetate. ExemplaryAlzheimer's Medications include, but are not limited to, Donezepil,Rivastigmine, and Galantamine. Exemplary analgesics include, but are notlimited to, Methadone, Hydromorphone, Oxymorphone, Buprenorphine,Hydrocodone, Morphine, and Hydrocodone. Exemplary GERD medicationsinclude, but are not limited to, esomeprazole, omeprazole, andpantoprazole. Exemplary anti-cholesterol agents include, but are notlimited to, ondansentron, pioglitazone, orlistat, lenalidomide,sofusbovir, rosuvastatin, amlodipine, simvastatin, and metformin.

The method provided herein may additionally produce a water- andsweat-resistant transdermal drug delivery system that comprises a patchthat is occlusive to one or more molecules. These molecules include, butare not limited to, caffeine, aripiprazole, theophylline, dyphilline,pentoxifyline, enprofylline, aminophylline, oxtriphylline, theobromine,propentofylline, xanthinol, doxofylline, pamabrom, lisofylline,ganciclovir, fenethylline, xanthine, uric acid, rolofylline, reproterol,cafedrine and theodrenaline, and any combination thereof.

The method provided herein produces a water- and sweat-resistanttransdermal drug delivery system that has a diameter between 1 and 8 cmin length, a surface area between 4 and 8 cm² and an onset of actionwithin 15 minutes of application to the skin of a mammal, and itsustainably delivers on or more active agents for 8-24 hours. The patchwithin the transdermal delivery system produced by the provided methodhas excellent adhesive strength, as shown by a peel rate of about 320mm/min, and allows diffusion of 65% to 100% of the active agent into theskin of a mammal within 8 to 24 hours. The mammal can be an animal or ahuman subject.

Methods of Treatment

Methods of treatment using the transdermal drug delivery system providedherein are also disclosed. Provided herein is a method of treatingseasonal allergic rhinitis in a subject in need thereof, wherein themethod comprises applying the water- and sweat-resistant transdermaldrug delivery system comprising one or more antihistamines to thesubject's skin, and maintaining the water- and sweat-resistanttransdermal drug delivery system in contact with the skin of the subjectfor 8-24 hours, thereby treating seasonal allergic rhinitis in thesubject. Exemplary antihistamines include, but are not limited to,diphenhydramine, desloratidine, cetirizine, loratadine, and anycombinations thereof. In some examples, the release rate of the one ormore antihistamines from the patch is 600 μg/cm²/hour during the firsthour of applying the patch. In some examples, the release rate of theone or more antihistamines from the patch is at least 100 μg/cm²/hourduring the entire time of applying the patch.

Also provided herein is a method of treating seasonal chronic idiopathicurticaria in a subject in need thereof, wherein the method comprisesapplying the water- and sweat-resistant transdermal drug delivery systemcomprising one or more antihistamines to the subject's skin, andmaintaining the water- and sweat-resistant transdermal drug deliverysystem in contact with the skin of the subject for 8-24 hours, therebytreating seasonal chronic idiopathic urticaria in the subject. Exemplaryantihistamines include, but are not limited to, diphenhydramine,desloratidine, cetirizine, loratadine, and any combinations thereof. Insome examples, the release rate of the one or more antihistamines fromthe patch is 600 μg/cm²/hour during the first hour of applying thepatch. In some examples, the release rate of the one or moreantihistamines from the patch is at least 100 μg/cm²/hour during theentire time of applying the patch.

Transdermal Drug Delivery System Comprising One or More Antihistamines

Also provided herein is a water- and sweat-resistant transdermal drugdelivery system, wherein the monolithic layer comprises 10-30% (w/w)chitosan; 10-40% (w/w) polyvinylpyrrolidone; 10-60% glycerol; 1-20%(w/w) gum Arabic; 10-50% (w/w) lactic acid, and a therapeuticallyeffective amount of one or more antihistamines. Exemplary antihistaminesinclude, but are not limited to, diphenhydramine, desloratidine,cetirizine, loratadine, and any combinations thereof. In some examples,the release rate of the one or more antihistamines from the patch is 600μg/cm²/hour during the first hour of applying the patch. In someexamples, the release rate of the one or more antihistamines from thepatch is at least 100 μg/cm²/hour during the entire time of applying thepatch. In some examples, the monolithic layer may further comprise 2-15%(w/w) of one or more fatty acids. The fatty acids include, but are notlimited to, tartaric acid, oleic acid, lauric acid, maleic acid, and anycombination thereof. In some examples, the monolithic layer may furthercomprise 2-15% (w/w) of one or more essential oils. Essential oilsinclude, but are not limited to, L-menthol, chuanxiong oil, clove oil,cinnamon oil, turpentine oil, eucalyptus oil, and any combinationthereof.

EXAMPLES Example 1: Method of Making a Transdermal Drug Delivery System

A liquid matrix comprising a layer of chitosan dissolved in lactic acid,glycerol and polyvinyl pyrrolidone is poured into a Teflon backing layerand solidified by solvent evaporation. The patch thus formed iscircular, and has a diameter of 4 cm. The backing layer and the matrixare equal in size. The chitosan and polyvinyl pyrrolidone matrix has afinal thickness of approximately 1 mm. See FIG. 2, first and third fromtop of figure.

In an alternative method, the transdermal drug delivery system comprisesa drug dispersed in an adhesive polymer matrix, which comprises a layerof chitosan dissolved in lactic acid, glycerol and polyvinylpyrrolidone. The liquid matrix is poured into a Teflon backing layer andsolidified by solvent evaporation. The matrix size is reduced to 3 cm,and then mounted on an additional backing layer, which has a diameter of4 cm. The edges of the Teflon backing layer are casted with a medicaladhesive to match the thickness of the matrix. See FIG. 2, second andfourth from top of figure.

Example 2: In Vitro Drug Diffusion Through a Skin Simulating Membrane

The permeation or flux of several drugs transdermally delivered to theskin was measured in vitro as a function of time using an artificialskin simulating membrane attached to a Franz diffusion cell at air-waterinterface. Several measurements were taken to determine the flux ofescitalopram oxalate, 4-aminopyridine, cetirizine dihydrochloride andaripiprazole over time. Modified Franz Diffusion Cells were filled with55 ml of phosphate buffer, and a skin simulating membrane was placed ineach cell at air-water interface and secured with a holed cap. The cellswere placed into a water bath and the temperature was equilibrated to38° C. The drug-loaded patch was gently placed onto the membrane andpressed down lightly. At different time points, the drug solution wascollected and replaced with fresh buffer, and ultraviolet (UV)absorbance was measured at 200-300 nm with clean quartz cuvettes, usingstandard curves to determine drug concentrations and cumulative drugrelease percentages over time. FIG. 3 shows that the system is permeableto the diffusion of escitalopram oxalate, 4-aminopyridine, andcetirizine dihydrochloride, but it is impermeable to the diffusion ofaripiprazole over time.

In view of these results, it was concluded that some drugs and smallmolecules may become “trapped” in the polymer matrix, and eitherprecipitate out of the patch, or re-crystallize within the film,resulting in an effectively inert patch with reduced adhesiveproperties, and with no drug delivering abilities. Further experimentsshowed that small molecules that cannot permeate into skin andbloodstream through the patch matrix include caffeine, aripiprazole,theophylline, dyphilline, pentoxifyline, enprofylline, aminophylline,oxtriphylline, theobromine, propentofylline, xanthinol, doxofylline,pamabrom, lisofylline, ganciclovir, fenethylline, xanthine, uric acid,rolofylline, reproterol, cafedrine and theodrenaline.

Example 3: In Vivo Drug Diffusion Through the Transdermal Drug DeliverySystem

The percentage diffusion of 4-aminopyridine through the transdermal drugdelivery system provided herein was measured over time, using differentpatch compositions. FIG. 4 shows the percentage diffusion of4-aminopyridine through a patch that consisted of 23% (w/w) glycerol,16% (w/w) gum Arabic, 11% (w/w) medium molecular weight chitosan, and48% (w/w) lactic acid. The patch was prepared by casting the liquidmatrix gel upon a suitable Teflon backing layer and drying for 18 hoursat 55° C. The resulting diffusion profiles indicate that the transdermaldrug delivery system provided herein allows permeation and diffusion of4-aminopyridine over time.

FIG. 5 shows the percentage diffusion of 4-aminopyridine through a patchthat consisted of 50% (w/w) glycerol, 14% (w/w) PVP, 18% (w/w) mediummolecular weight chitosan, and 18% (w/w) lactic acid. The patch wasprepared by casting the liquid matrix gel upon a suitable Teflon backinglayer and drying for 3 hours at 80° C. The resulting diffusion profilesindicate that the transdermal drug delivery system provided hereinallows permeation and diffusion of 4-aminopyridine over time.

FIG. 6 shows the percentage diffusion of 4-aminopyridine through a patchthat consisted of 36% (w/w) glycerol, 15.3% PVP, 0.7% (w/w) gum Arabic,9.5% (w/w) medium molecular weight chitosan, and 38.5% (w/w) lacticacid. The patch was prepared by casting the liquid matrix gel upon asuitable Teflon backing layer and drying for 5 hours at 80° C. Theresulting diffusion profiles indicate that the transdermal drug deliverysystem provided herein allows permeation and diffusion of4-aminopyridine over time.

Example 4: Treatment of Allergic Rhinitis by Transdermal Drug Delivery

A human subject suffering from severe symptoms of seasonal allergicrhinitis is treated with an antihistamine cocktail that comprisesdiphenhydramine, desloratidine, cetirizine, and loratadine. Theantihistamine cocktail is administered transdermally to the skin of thehuman subject by applying the disclosed water- and sweat-resistanttransdermal drug delivery system. The water- and sweat-resistanttransdermal drug delivery system is maintained in contact with the skinof the subject for 24 hours. At the end of the treatment, the subject isfree of symptoms associated with seasonal allergic rhinitis and presentsno relapse even after renewed exposure to allergens.

In view of the many possible embodiments to which the principles of ourinvention may be applied, it should be recognized that illustratedembodiments are only examples of the invention and should not beconsidered a limitation on the scope of the invention. Rather, the scopeof the invention is defined by the following claims. We therefore claimas our invention all that comes within the scope and spirit of theseclaims.

1-14. (canceled)
 15. A method of making a water- and sweat-resistanttransdermal drug delivery system, wherein the method comprises firstadding a film-forming agent and a plasticizer to water and stirring themixture at room temperature (25° C.); gradually adding a bioadhesivepolymer and a naturally occurring polysaccharide and stir the mixtureuntil the bioadhesive polymer is dissolved and viscosity is reduced;adding a film-forming agent and a keratolytic agent and stirring for 2-5hours until an even mixture is obtained; adding one or more activeagents and stirring the mixture for 1-4 hours to obtain a formulation;casting the formulation onto an array of backing layers; and baking thebacking layers at 80° C. for 4-8 hours, thereby making a water- andsweat-resistant transdermal drug delivery system.
 16. The method ofclaim 15, wherein the bioadhesive polymer is chitosan,hydroxypropylmethyl cellulose, hydroxyethyl cellulose, xanthan gum, guargum, sodium alginate, or a combination thereof.
 17. The method of claim15, wherein the film-forming agent is polyvinyl alcohol, polyvinylpyrrolidone, carrageenan, gelatin, dextrin, polyethylene oxide, guargum, xanthan gum, or a combination thereof.
 18. The method of claim 15,wherein the plasticizer is glycerol, sorbitol, polyethylene glycol,polypropylene glycol, polyethylene-propylene glycol, or a combinationthereof.
 19. The method of claim 15, wherein the naturally occurringpolysaccharide is agar, alginate, chitin, glucomannan, gellan gum,gelatin, gum guar, gum Arabic, locust bean gum, pectin, xanthan, or acombination thereof.
 20. The method of claim 15, wherein the keratolyticagent is urea, lactic acid, allantoin, benzoyl peroxide, salicyclicacid, or a combination thereof.
 21. The method of claim 15, wherein thebioadhesive polymer is chitosan; the film-forming agent ispolyvinylpyrrolidone; the plasticizer is glycerol; the naturallyoccurring polysaccharide is gum Arabic; and the keratolytic agent islactic acid.
 22. The method of claim 15, wherein the backing layerscomprise Teflon, a metal foil, a metalized polyfoil, a composite foil, afilm containing polyester, or a foam.
 23. The method of claim 15,wherein the active agent is one or more of an antihistamine, a potassiumchannel blocker, an analgesic agent, an antidiabetic agent, apain-relief agent, an antidepressant agent, an antipsychotic agent, ananti-Parkinsonian agent, a vasodilator, a diuretic, a calcium channelblocker, an anti-acne agent, an anti-aging agent, an antibiotic agent,an antifungal agent, an ACE inhibitor, a GERD medication, ananti-inflammatory agent, an opioid, an anti-asthma agent, acorticosteroid, a nicotinic cholinergic receptor agonist, ananti-oxidant agent, an antiprotozoal agent, an antipruritic agent, anantiviral agent, a chemotherapeutic agent, an immunomodulatory agent, akeratolytic agent, a retinoid, or a central nervous system stimulant.24. The method of claim 15, wherein the active agent is one or more ofDiphenhydramine, Desloratadine, Cetirizine, Loratadine, Trihexyphenidyl,Asenapine, Prostacyclin, Buspirone, Butorphanol, Captopril, Carbidopa,Albuterol, Naltrexone, Ivabradine, Dexamethasone, Phenylephrine,Fluocinolone acetonide, Dexlansoprazole, Furosemide, Isradipine,Venlafaxine, or Enalapril.
 25. The method of claim 15, wherein the patchhas a diameter between 1 and 8 cm in length, a surface area between 4and 8 cm² and an onset of action within 15 minutes, and sustainablydelivers on or more active agents for 8-24 hours; and wherein the patchhas a peel rate of about 320 mm/min.
 26. The method of claim 15, whereinthe patch is occlusive to caffeine, aripiprazole, theophylline,dyphilline, pentoxifyline, enprofylline, aminophylline, oxtriphylline,theobromine, propentofylline, xanthinol, doxofylline, pamabrom,lisofylline, ganciclovir, fenethylline, xanthine, uric acid,rolofylline, reproterol, cafedrine and theodrenaline, or any combinationthereof.
 27. The method of claim 15, wherein 65% to 100% of the activeagent diffuses into the skin of a mammal within 8 to 24 hours.
 28. Themethod of claim 15, wherein the mammal is a human subject. 29-48.(canceled)